The objective of this application is to develop innovative tumor- targeted therapies for lung cancer and bronchial premalignancy. The general hypothesis is that therapeutic strategies that combine anatomical and molecular targeting should constitute improved therapeutic modalities for these conditions. Three major therapeutic strategies will be pursued: 1) inhaled therapeutics for bronchial premalignancy, 2) inhibition of pathways that play a major role in lung cancer dysregulated growth, and 3) anatomical targeting. Three prototype projects within these three major strategies are proposed: 1) preclinical and initial clinical evaluation of an aerosolized liposome/p53 formulation in patients with lung cancer and bronchial premalignancy carrying p53 mutations, 2) clinical studies of synergism between chemotherapy and the anti-EGFR monoclonal antibody C225 in stage IIIA NSCLC, and 3) integration of intrapleural therapy in the treatment of patients with stage IIB NSCLC with malignant pleural effusion. All three projects include the performance of clinical trials that incorporate the measurement of pharmacological or molecular parameters potentially correlated with the observed antitumor effect. The work proposed is a logical continuation of the applicant's translational research efforts in the areas of drug delivery and lung cancer therapy research during the last decade. The specific projects will be conducted by young clinical investigators mentored by the applicant. Candidates for mentorship under this proposal will include fellows enrolled in the Medical Oncology fellowship at NYU and junior staff members of the Divisions of Hematology, Pulmonary Medicine, and Surgery. Four such candidates have already been identified. It is anticipated that a total of ten young clinical investigators will be mentored during a five-year period.